EZH2 在调控 rRNA 2'-O 甲基化和 IRES 依赖翻译中的 PRC2 非依赖性功能。

A PRC2-independent function for EZH2 in regulating rRNA 2'-O methylation and IRES-dependent translation.

机构信息

Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.

Basic and Translational Research Division, Department of Cardiology, Boston Children's Hospital, Boston, MA, USA.

出版信息

Nat Cell Biol. 2021 Apr;23(4):341-354. doi: 10.1038/s41556-021-00653-6. Epub 2021 Apr 1.

Dysregulated translation is a common feature of cancer. Uncovering its governing factors and underlying mechanism are important for cancer therapy. Here, we report that enhancer of zeste homologue 2 (EZH2), previously known as a transcription repressor and lysine methyltransferase, can directly interact with fibrillarin (FBL) to exert its role in translational regulation. We demonstrate that EZH2 enhances rRNA 2'-O methylation via its direct interaction with FBL. Mechanistically, EZH2 strengthens the FBL-NOP56 interaction and facilitates the assembly of box C/D small nucleolar ribonucleoprotein. Strikingly, EZH2 deficiency impairs the translation process globally and reduces internal ribosome entry site (IRES)-dependent translation initiation in cancer cells. Our findings reveal a previously unrecognized role of EZH2 in cancer-related translational regulation.

翻译

翻译后失调是癌症的一个常见特征。揭示其调控因素和潜在机制对于癌症治疗至关重要。在这里，我们报告称，先前被认为是转录抑制剂和赖氨酸甲基转移酶的增强子结合抑制因子 2（EZH2）可以与核仁蛋白 FBL（fibrillarin）直接相互作用，从而在翻译调控中发挥作用。我们证明 EZH2 通过与 FBL 的直接相互作用增强 rRNA 2'-O 甲基化。在机制上，EZH2 增强了 FBL-NOP56 的相互作用，并促进了框 C/D 小核仁核糖核蛋白的组装。引人注目的是，EZH2 缺陷会全局损害翻译过程，并降低癌细胞中内部核糖体进入位点（IRES）依赖性翻译起始。我们的发现揭示了 EZH2 在癌症相关翻译调控中的一个以前未被认识的作用。